title: Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy.
abstract: Although endothelin-receptor antagonists reduce albuminuria in diabetic nephropathy, fluid retention limits their use. Here, we examined the effect of atrasentan, a selective endothelin A receptor (ET(A)R) antagonist, on albuminuria in a randomized, double-blind, placebo-controlled trial of subjects with diabetic nephropathy already receiving stable doses of renin-angiotensin system (RAS) inhibitors. We randomly assigned 89 subjects with eGFR >20 ml/min per 1.73 m(2) and a urinary albumin-to-creatinine ratio (UACR) of 100 to 3000 mg/g to placebo or atrasentan (0.25, 0.75, or 1.75 mg daily) for 8 weeks. Compared with placebo, atrasentan significantly reduced UACR only in the 0.75- and 1.75-mg groups (P=0.001 and P=0.011, respectively). Compared with the 11% reduction in the geometric mean of the UACR from baseline to final observation in the placebo group during the study, the geometric mean of UACR decreased by 21, 42, and 35% in the 0.25-, 0.75-, and 1.75-mg atrasentan groups (P=0.291, P=0.023, and P=0.073, respectively). In the placebo group, 17% of subjects achieved ≥40% reduction in UACR from baseline compared with 30, 50, and 38% in the 0.25-, 0.75-, and 1.75-mg atrasentan groups, respectively (P=0.029 for 0.75 mg versus placebo). Peripheral edema occurred in 9% of subjects receiving placebo and in 14, 18, and 46% of those receiving 0.25, 0.5, and 1.75 mg atrasentan, respectively (P=0.007 for 1.75 mg versus placebo). In summary, atrasentan, at the doses tested, is generally safe and effective in reducing residual albuminuria and may ultimately improve renal outcomes in patients with type 2 diabetic nephropathy.
authors.affiliation: Division of Nephrology, University of Utah Health Sciences Center, 1900 East 30 North, Salt Lake City, UT 84132, USA. donald.kohan@hsc.utah.edu
authors.forename: Donald E
authors.initials: DE
authors.lastname: Kohan
authors.forename: Yili
authors.initials: Y
authors.lastname: Pritchett
authors.forename: Mark
authors.initials: M
authors.lastname: Molitch
authors.forename: Shihua
authors.initials: S
authors.lastname: Wen
authors.forename: Tushar
authors.initials: T
authors.lastname: Garimella
authors.forename: Paul
authors.initials: P
authors.lastname: Audhya
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Andress
mesh_terms: D000368:Aged; D000419:Albuminuria / Q000188:drug therapy* / Q000453:epidemiology / Q000209:etiology*; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000077868:Atrasentan; D003928:Diabetic Nephropathies / Q000150:complications* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D065130:Endothelin A Receptor Antagonists; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D065130:Endothelin A Receptor Antagonists; D011759:Pyrrolidines; D000077868:Atrasentan